Regulatory T Cells and Their Prognostic Relevance in Hematologic Malignancies

D’Arena, Giovanni; Vitale, Candida; Coscia, Marta; Festa, Agostino; Di Minno, Nicola Matteo Dario; De Feo, Vincenzo; Caraglia, Michele; Calapai, Gioacchino; Laurenti, Luca; Musto, Pellegrino; Di Minno, Giovanni; Fenoglio, Daniela

doi:https://doi.org/10.1155/2017/1832968

Journal of Immunology Research

On this page

Abstract Introduction Conclusions Conflicts of Interest References Copyright Related Articles

Special Issue

Inflammation in the Tumor Microenvironment

View this Special Issue

Review Article | Open Access

Volume 2017 | Article ID 1832968 | https://doi.org/10.1155/2017/1832968

Regulatory T Cells and Their Prognostic Relevance in Hematologic Malignancies

Giovanni D’Arena,¹Candida Vitale,^2,3Marta Coscia,^2,3Agostino Festa,⁴Nicola Matteo Dario Di Minno,⁵Vincenzo De Feo,⁶Michele Caraglia,⁴Gioacchino Calapai,⁷Luca Laurenti,⁸Pellegrino Musto,⁹Giovanni Di Minno,⁵and Daniela Fenoglio¹⁰

Academic Editor: Wenxin Zheng

Received17 Aug 2017

Accepted14 Nov 2017

Published21 Dec 2017

Abstract

Regulatory T cells (Tregs) have a fundamental function in monitoring the immune homeostasis in healthy individuals. In cancer and, in particular, in hematological malignancies, Tregs exert a major immunosuppressive activity, thus playing a critical role in tumor cell growth, proliferation, and survival. Here, we summarize published data on the prognostic significance of Tregs in hematological malignancies and show that they are highly conflicting. The heterogeneity of the experimental approaches that were used explains—at least in part—the discordant results reported by different groups that have investigated the role of Tregs in cancer. In fact, different tissues have been studied (i.e., peripheral blood, bone marrow, and lymph node), applying different methods (i.e., flow cytometry versus immunohistochemistry, whole blood versus isolated peripheral blood mononuclear cells versus depletion of CD25⁺ cells, various panels of monoclonal antibodies, techniques of fixation and permeabilization, and gating strategies). This is of relevance in order to stress the need to apply standardized approaches in the study of Tregs in hematological malignancies and in cancer in general.

1. Introduction

Regulatory T cells (Tregs) constitute a small-size subpopulation of CD4⁺ T cells, accounting for 1–4% of circulating CD4⁺ lymphocyte in humans, specialized in suppressive functions that control unwanted immune responses not only toward self-antigens but also toward foreign antigens in the context of the immune tolerance [1].

Gershon and Kondo from Yale University first proposed the existence of CD8⁺ T cells with suppressive activity more than 40 years ago [2]. However, after the initial great interest following this first report, due to the fact that a precise definition of Tregs lacked for several years, no further advances in the study of this cell population were made for decades. In 1995, Sakaguchi and coworkers identified Tregs in mouse as CD4⁺ T cells expressing surface interleukin-2 (IL-2) receptor α-chain (CD25) [3]. Baecher-Allan and coworkers, using flow cytometry and analyzing sorted cells in vitro, identified a very small subset of T cells with high expression of CD25 and regulatory function in humans [4]. However, CD25 is not exclusively restricted to Tregs, and its surface expression is also seen on effector T lymphocytes after activation [5]. The intracytoplasmic Forkhead helix box P3 (FoxP3), a transcription factor required for the development, maintenance, and function of Tregs was subsequently identified [6, 7]. The central role of this transcription factor is confirmed by the fact that a FoxP3 single gene mutation on the X chromosome induces in Scurfy mice a severe autoimmune/inflammatory disease. In humans, the same mutation causes a disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), characterized by autoimmune manifestations in multiple endocrine organs, such as diabetes and thyroiditis, inflammatory bowel disease, and severe allergies [8]. Finally, the absence of the heterodimeric IL-7 receptor (CD127) combined with CD4, CD25, and FoxP3, has been shown to better identify Tregs, avoiding the contamination from other cell populations such as activated effector T cells [9, 10].

2. Regulatory T Cells and Prognostic Significance in Cancer

The role of Tregs in cancer appears to be relevant by promoting tumor progression and suppressing effective antitumor activity [11–13]. Overall, the large majority of studies report that the frequency and the suppressive function of Tregs are increased in cancer patients as compared to healthy subjects. However, some issues are still a matter of debate, in particular the prognostic significance of this cell subpopulation. In general, Tregs predict poor outcome in cancer patients [12], but some reports have shown that higher Treg numbers and preserved activity are associated with a better prognosis [14–16].

This review stems from the need to reassess the topic of prognostic relevance of Tregs in cancer, focusing on patients with hematologic malignancies. For this purpose, we reviewed a large body of published papers conducting a PubMed literature search (keywords: Regulatory T cells, Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, monoclonal gammopathies, myelofibrosis, essential thrombocythemia, polycythemia vera, and Ph1-negative chronic myeloproliferative neoplasms).

3. Regulatory T Cells in Chronic Lymphocytic Leukemia

The accumulation of monoclonal B lymphocytes in the bone marrow, lymphoid organs, and peripheral blood is the hallmark of chronic lymphocytic leukemia (CLL), the most common form of leukemia in Western countries [17]. The importance of T cell dysregulation in the pathogenesis and development of CLL is now well established [18, 19], and in this setting, the role of Tregs has also been investigated [20, 21]. As shown in Table 1, several authors reported data on Tregs in CLL showing in the majority of cases an expansion of this population [22–31]. In addition, a correlation between higher Treg numbers and more aggressive clinical-biological features and adverse prognosis of CLL has been described.

As previously discussed [20], the reported percentage of Tregs in CLL is highly variable. According to the majority of reports, the percentage of Tregs is higher in CLL patients than in normal controls, and when the absolute number is considered, Tregs are always found to be significantly greater in CLL as compared to healthy donors.

Interestingly, based on their experimental work, Jak et al. speculated that the accumulation of Tregs in CLL is due to an increased proliferation induced by CD27/CD70 interaction in the lymph node proliferation centers and to a decreased sensitivity to apoptosis [22].

Dasgupta et al. tried to establish an optimal threshold level for prognostic purpose [28]. The cut-off was assessed by receiver operating characteristic (ROC) analysis. A cut-off of 5.7% and 35 cells/μL for percentage and absolute Treg count, respectively, were determined as optimal in patients with CLL, along with a median Tregs percentage of 15.5% used to separate low- and high-risk patients. Using the same approach in the setting of Rai stage 0 CLL patients, our group found that the absolute number of Tregs was an independent predictor of time to the first treatment, with the best predictive cut-off being 41 cells/μL [24]. Overall, these data show that the absolute Treg number is able to identify Rai stage 0 CLL patients at higher risk of requiring therapy.

Rissiek et al., applying a multidimensional scaling analysis to assess the composition of the circulating T cell populations, generated T cell scores showing that suppressive T cell profiles emerge early during monoclonal B cell lymphocytosis (MBL), the well-recognized pre-CLL stage [31–33]. As the disease evolves from MBL to overt and advanced CLL, specific sequential changes in T cells appear, progressively compromising the effector T cells function and contributing to disease progression [30].

In our hands too, the absolute number of Tregs in MBL patients was lower compared to CLL patients, but slightly higher than healthy controls [30]. In addition, the absolute Treg cell number directly correlated with more advanced CLL clinical stages and higher circulating B cell numbers. Of note, the absolute number of Tregs was lower in MBL patients as compared to early-stage CLL patients (0/A according to Rai/Binet stage). In summary, Treg numbers increase gradually from normal subjects to “clinical” MBL patients and are significantly higher in CLL patients as compared to MBL patients.

Regarding the functional properties, some authors reported a reduced inhibitory function of Tregs in CLL [27, 34]. On the contrary, Piper et al. showed that in CLL patients Tregs retain their function and are not influenced by chemotherapy [35]. A correlation between a higher circulating Treg numbers and dysfunctional Vγ9Vδ2 T cells in untreated CLL patients was also shown, thus corroborating the hypothesis that Tregs may not be only bystanders but have a functional role in this setting [36].

A normalization in Treg number was observed after fludarabine therapy [34], and also in CLL patients treated with lenalidomide, suggesting that such drugs are able to modulate cell-mediated immunity in CLL [37].

Finally, we also tested the ability of green tea, a popular beverage in China, Japan, and increasingly used in Western countries, to modulate Treg number in peripheral blood of CLL patients in the early phases of the disease, for which at the present time there is no effective intervention and a “wait and see” policy is generally adopted [38, 39]. We showed that the B cell lymphocyte count and the absolute circulating Treg number were reduced after 6-month consumption of oral green tea extract, suggesting that this compound can modulate circulating Tregs in CLL patients with early stage of disease and delay disease progression.

4. Regulatory T Cells in Lymphomas and Monoclonal Gammopathies

The neoplastic lymph nodes in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) contain not only neoplastic B cells but also nontumoral T cells, macrophages, and dendritic cells, constituting the so-called tumor microenvironment. The importance of the microenvironment in the pathogenesis and progression of lymphomas is still a matter of debate and many studies have focused on the role of its different components, including Tregs. Tregs are increased in lymphoma tissues and are able to inhibit cytotoxic CD8⁺ T cells exposed to lymphoma B cells [40].

Marshall et al. showed that HL-infiltrating lymphocytes are highly enriched in Tregs, which induce a profoundly immunosuppressive environment [41]. This was confirmed by Schreck et al. who demonstrated that in classical HL the microenvironment is dominated by Th2 cells and Tregs [42]. Moreover, a high ratio of Tregs over Th2 cells resulted in a significantly shortened disease-free survival.

However, conflicting results have been reported regarding the prognostic significance of Tregs infiltration in both HL and NHL. In fact, whereas in follicular lymphoma (FL), the most common form of low-grade NHL, germinal center (GC) diffuse large B cell lymphomas (DLBCL), and HL, an intrafollicular infiltration of Tregs, has a positive prognostic significance; this is not true in the case of non-GC-type DLBCL [43]. Moreover, as shown in Table 2, in some reports, a higher number of Tregs correlates with a good prognosis, while in other, it does not [43–49]. Of interest, Kim et al. evaluating Tregs on node biopsy of extranodal natural killer/T cell lymphomas showed that patients with poor performance status and with non-upper aerodigestive tract had a decreased number of Tregs (<50/0.40 mm²), while an increased number (>50/0.40 mm²) was associated with prolonged overall survival and progression-free survival [48]. Finally, Carreras et al. reported that the median Treg number in patients with FL at diagnosis had a median cell percentage of 10.5% [49]. Furthermore, patients were classified as having Tregs > 10%, 5–10%, and <5% with a 5-year overall survival of 80%, 74%, and 50%, respectively. Patients with transformed DLBCL showed lower Treg number with respect to patients with grades 1–3 FL.

Regarding the frequency and prognostic significance of Tregs, conflicting results have also been obtained in the field of monoclonal gammopathies (Table 3). In some reports, Tregs were found to be increased in frequency, while in others they were reduced or comparable with respect to healthy subjects [50]. Again, some authors reported a correlation with tumour burden and with worse prognosis, but this was not consistent among different publications [50–57]. We recently published our data on the flow cytometric evaluation of Tregs in multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS) [51]. We found no differences in Treg frequency in MM and MGUS with respect to normal controls, and no correlations with main clinical and laboratory features in this disease setting were observed.

5. Regulatory T Cells in Acute Leukemias, Chronic Myeloid Leukemia, and Ph1-Negative Chronic Myeloproliferative Neoplasms

Few studies have been published regarding the role of Tregs in acute myeloid and lymphoid leukemias (Table 4) [58–61]. In a study by Bhattacharya et al., an increased number of Tregs was found in patients with B cell acute lymphoblastic leukemia (B-ALL), and a correlation with disease progression was highlighted [58].

Regarding chronic myeloid leukemia (CML), an interesting paper has been published by Zahran and Badrawy, in which Tregs were found increased in the peripheral blood of affected individuals as compared to controls. Moreover, Tregs frequency correlated with the level of BCR/ABL, basophil number, blast cell count, and Sokal score, and Treg number was higher in accelerated and blastic phase with respect to chronic phase [62]. Of note, Treg frequency declined after therapy with imatinib. Rojas et al. found a lower Treg number in patients who achieved a complete cytogenetic response [63], while higher Treg frequencies were found after stem cell transplant compared to normal controls and newly diagnosed patients [64]. Finally, the correlations with Sokal score and basophil number were validated by other studies [65, 66], whereas the impact of treatment has not been confirmed, since no changes in Treg frequency was observed after 6 months of tyrosine kinase inhibitors therapy [65]. Table 5 summarizes the results of studies analyzing Tregs in CML.

Hasselbalch et al. studied patients with Ph1-negative chronic myeloproliferative neoplasms and found that circulating Tregs were significantly expanded in patients treated with IFN-α2 with respect to healthy donors and in patients treated with hydroxyurea [66]. Kovacsovics-Bankowski et al. analyzed patients with polycythemia vera (PV) and essential thrombocythemia (ET) and found increased numbers of circulating Tregs and an enrichment in highly suppressive subsets (defined as CD39⁺/HLA-DR⁺) in patients treated with PegIFN-α with respect to those treated with hydroxyurea [67]. Moreover, molecular nonresponder patients showed a trend towards increased frequency of Tregs compared to responder patients, but no changes were observed in terms of absolute numbers of Tregs. Overall, a positive correlation between proliferating Tregs (Ki-67⁺), highly suppressive Tregs (CD39⁺/HLA-DR⁺), and JAK2^V617F allelic burden was found, thus suggesting that the lack of ability of PegIFN-α treatment to decrease circulating Tregs predicts a poor molecular response.

Primary myelofibrosis (PMF) is a clonal disease of the hematopoietic stem cell characterized by a variable degree of bone marrow fibrosis, splenomegaly, and an increased risk of leukemic transformation. Contradictory data about Tregs in PMF have been published (Table 6). Massa et al. reported a reduced frequency and absolute number of Tregs in PMF than in normal controls [68]. No association with clinical-biological features of the disease was found, but a correlation between reduced Treg frequency and longer disease duration in patients with CALR mutation genotype was described. In these patients, a higher Treg frequency is significantly associated with advanced disease, higher IPSS/DIPSS score, and lower hemoglobin concentration. The same authors later documented the effect of ruxolitinib on Treg frequency, showing that the treatment with this small-molecule JAK1/2 inhibitor leads to a profound and long-lasting reduction in the frequency of circulating Tregs [69]. Wang et al. found no significant differences in the number of Tregs in patients with primary or post-ET myelofibrosis [70]. However, they reported that ruxolitinib significantly inhibits the release of sIL2-Rα, an inflammatory cytokine produced by Tregs, contributing to the clinical improvement of constitutional symptoms induced by the drug. These data have been further confirmed by an in vitro study in which the JAK1/2 inhibition by ruxolitinib was able to prevent Treg differentiation [71]. Table 6 summarizes the results of studies analyzing Tregs in Ph1-negative chronic myeloproliferative neoplasms.

6. Conclusions

Tregs have a fundamental function in maintaining the immune homeostasis in healthy individuals. In cancer and in particular in hematological malignancies, Tregs exert a major immunosuppressive activity, thus playing a critical role in tumor cell growth, proliferation, and survival. Published data on the prognostic significance of the Treg number in hematological malignancies show conflicting results. In our opinion, this variability reported by different groups is most likely explained by the heterogeneity of the experimental approaches that are used. In fact, different tissues have been studied (i.e., peripheral blood, bone marrow, and lymph node) and different analytic methodologies have been applied (i.e., flow cytometry versus immunohistochemistry). Moreover, while some authors studied the whole blood compartment, others evaluated the Treg population in isolated peripheral blood mononuclear cells or in a CD25-depleted subpopulation. Finally, various panels of markers, different techniques of fixation and permeabilization, and several gating strategies have been applied. This is of relevance to stress the need to apply standardized approaches in the study of Tregs in hematological malignancies and in cancer in general.

In perspective, in light of the increasing evidence of the important role of Tregs in immune evasion mechanism exerted by tumor cells, therapeutic interventions targeting intratumoral Treg infiltrates may be conceived in order to fight cancer. Treg inhibition or depletion, the latter uses monoclonal antibodies targeting surface antigens on Tregs such as CD25, is currently under investigation [72].

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

S. Sakaguchi, K. Wing, and M. Miyara, “Regulatory T cells – a brief history and perspective,” European Journal of Immunology, vol. 37, Supplement 1, pp. S116–S123, 2007.
View at: Publisher Site | Google Scholar
R. K. Gershon and K. Kondo, “Cell interactions in the induction of tolerance: the role of thymic lymphocytes,” Immunology, vol. 18, no. 5, pp. 723–737, 1970.
View at: Google Scholar
S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, and M. Toda, “Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chain (CD25). breakdown of a single mechanism of self-tolerance causes various autoimmune disease,” Journal of Immunology, vol. 155, pp. 1151–1164, 1995.
View at: Google Scholar
C. Baecher-Allan, J. A. Brown, G. J. Freeman, and D. A. Hafler, “CD4⁺CD25^high regulatory cells in human peripheral blood,” Journal of Immunology, vol. 167, no. 3, pp. 1245–1253, 2001.
View at: Publisher Site | Google Scholar
R. J. Robb, A. Munck, and K. A. Smith, “T cell growth factor receptors. Quantitation, specificity, and biological relevance,” Journal of Experimental Medicine, vol. 154, no. 5, pp. 1455–1474, 1981.
View at: Publisher Site | Google Scholar
S. Hori, T. Numura, and S. Sakaguchi, “Control of regulatory T cell development by the transcription factor FoxP3,” Science, vol. 299, no. 5609, pp. 1057–1061, 2003.
View at: Publisher Site | Google Scholar
J. D. Fontenot, M. A. Gavin, and A. Y. Rudensky, “FoxP3 programs the development and function of CD4⁺CD25⁺ regulatory T cells,” Nature Immunology, vol. 4, no. 4, pp. 330–336, 2003.
View at: Publisher Site | Google Scholar
C. L. Bennett, J. Christie, F. Ramsdell et al., “The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3,” Nature Genetics, vol. 27, no. 1, pp. 20-21, 2001.
View at: Publisher Site | Google Scholar
N. Seddiki, B. Santner-Nanan, J. Martinson et al., “Expression of interleukin (IL)-2 and IL-7 receptors discriminate between human regulatory and activated T cells,” Journal of Experimental Medicine, vol. 203, no. 7, pp. 1693–1700, 2006.
View at: Publisher Site | Google Scholar
W. Liu, A. L. Putnam, Z. Xu-Yu et al., “CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4⁺ Treg cells,” Journal of Experimental Medicine, vol. 203, pp. 1701–1711, 2006.
View at: Publisher Site | Google Scholar
M. Beyer and J. L. Schultze, “Regulatory T cells in cancer,” Blood, vol. 108, no. 3, pp. 804–811, 2006.
View at: Publisher Site | Google Scholar
T. L. Whiteside, “The role of regulatory T cells in cancer immunology,” ImmunoTargets and Therapy, vol. 4, pp. 159–171, 2015.
View at: Publisher Site | Google Scholar
Y. Takeuchi and H. Nishikawa, “Roles of regulatory T cells in cancer immunity,” International Immunology, vol. 28, no. 8, pp. 401–409, 2016.
View at: Publisher Site | Google Scholar
J. Wang and X. Y. Ke, “The Four types of Tregs in malignant lymphomas,” Journal Hematological & Oncology, vol. 4, p. 50, 2011.
View at: Publisher Site | Google Scholar
P. Farinha, A. Al-Tourah, K. Gill, R. Klasa, J. M. Connors, and R. D. Gascoyne, “The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation,” Blood, vol. 115, no. 2, pp. 289–295, 2010.
View at: Publisher Site | Google Scholar
R. Droeser, I. Zlobec, E. Kilic et al., “Differential pattern and prognostic significance of CD4⁺, FOXP3⁺ and IL-7⁺ tumor infiltrating lymphocytes in ductal and lobular breast cancers,” BMC Cancer, vol. 12, no. 1, p. 134, 2012.
View at: Publisher Site | Google Scholar
N. Chiorazzi, K. R. Rai, and M. Ferrarini, “Chronic lymphocytic leukemia,” New England Journal of Medicine, vol. 352, no. 8, pp. 804–815, 2005.
View at: Publisher Site | Google Scholar
F. Forconi and P. Moss, “Perturbation of the normal immune system in patients with CLL,” Blood, vol. 126, no. 5, pp. 573–581, 2015.
View at: Publisher Site | Google Scholar
M. E. Wallace, M. B. Alcantara, M. Yosuke, G. Kannourakis, and S. P. Berzins, “An emerging role for immune regulatory subsets in chronic lymphocytic leukaemia,” International Immunopharmacology, vol. 28, no. 2, pp. 897–900, 2015.
View at: Publisher Site | Google Scholar
G. D’Arena, V. Simeon, F. D’Auria et al., “Regulatory T-cells in chronic lymphocytic leukemia: actor or innocent bystander?” American Journal of Blood Research, vol. 3, no. 1, pp. 52–57, 2013.
View at: Google Scholar
G. D'Arena, G. Rossi, B. Vannata et al., “Regulatory T-cells in chronic lymphocytic leukemia and autoimmune diseases,” Mediterranean Journal of Hematology and Infectious Diseases, vol. 4, no. 1, article e2012053, 2012.
View at: Publisher Site | Google Scholar
M. Jak, R. Mous, E. B. Remmerswaal et al., “Enhanced formation and survival of CD4⁺ CD25^hi FoxP3⁺ T-cells in chronic lymphocytic leukemia,” Leukemia & Lymphoma, vol. 50, no. 5, pp. 788–801, 2009.
View at: Publisher Site | Google Scholar
G. D’Arena, L. Laurenti, M. M. Minervini et al., “Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease,” Leukemia Research, vol. 35, no. 3, pp. 363–368, 2011.
View at: Publisher Site | Google Scholar
G. D’Arena, F. D’Auria, V. Simeon et al., “A shorter time to the first treatment may be predicted by the absolute number of regulatory T-cells in patients with Rai stage 0 chronic lymphocytic leukemia,” American Journal of Hematology, vol. 87, no. 6, pp. 628–631, 2012.
View at: Publisher Site | Google Scholar
L. Weiss, T. Melchardt, A. Egle, C. Grabmer, R. Greil, and I. Tinhofer, “Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia,” Cancer, vol. 117, no. 10, pp. 2163–2169, 2011.
View at: Publisher Site | Google Scholar
D. P. Lad, S. Varma, N. Varma, M. U. Sachdeva, P. Bose, and P. Malhotra, “Regulatory T-cells in B-cell chronic lymphocytic leukemia: their role in disease progression and autoimmune cytopenias,” Leukemia and Lymphoma, vol. 54, pp. 1012–1019, 2013.
View at: Publisher Site | Google Scholar
A. Biancotto, P. K. Dagur, J. C. Fuchs, A. Wiestner, C. B. Bagwell, and J. P. McCoy Jr., “Phenotypic complexity of T regulatory subsets in patients with B-chronic lymphocytic leukemia,” Modern Pathology, vol. 25, no. 2, pp. 246–259, 2012.
View at: Publisher Site | Google Scholar
A. Dasgupta, M. Mahapatra, and R. Saxena, “A study for proposal of use of regulatory T cells as a prognostic marker and establishing an optimal threshold level for their expression in chronic lymphocytic leukemia,” Leukemia & Lymphoma, vol. 56, no. 6, pp. 1831–1838, 2015.
View at: Publisher Site | Google Scholar
V. E. Mpakou, H. D. Ioannidou, E. Konsta et al., “Quantitative and qualitative analysis of regulatory T cells in B cell chronic lymphocytic leukemia,” Leukemia Research, vol. 60, pp. 74–81, 2017.
View at: Publisher Site | Google Scholar
G. D’Arena, G. Rossi, M. M. Minervini et al., “Circulating regulatory T cells in “clinical” monoclonal B-cell lymphocytosis,” International Journal of Immunopathology and Pharmacology, vol. 24, no. 4, pp. 915–923, 2011.
View at: Publisher Site | Google Scholar
A. Rissiek, C. Schulze, U. Bacher et al., “Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T-cells in chronic lymphocytic leukemia,” International Journal Cancer, vol. 135, pp. 2370–2379, 2014.
View at: Publisher Site | Google Scholar
D. Rossi, E. C. Sozzi, A. Puma et al., “The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukemia and is recapitulated by biological risk factors,” British Journal of Haematology, vol. 146, no. 1, pp. 64–75, 2009.
View at: Publisher Site | Google Scholar
G. D’Arena and P. Musto, “Monoclonal B-cell lymphocytosis,” Translational Medicine, vol. 8, pp. 75–79, 2014.
View at: Google Scholar
M. Beyer, M. Kochanek, K. Darabi et al., “Reduced frequencies and suppressive function of CD4⁺CD25^hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine,” Blood, vol. 106, no. 6, pp. 2018–2025, 2005.
View at: Publisher Site | Google Scholar
K. P. Piper, M. Karanth, A. McLarnon et al., “Chronic lymphocytic leukaemia cells drive the global CD4⁺ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4⁺ forkhead box P3⁺ T cells,” Clinical & Experimental Immunology, vol. 166, no. 2, pp. 154–163, 2011.
View at: Publisher Site | Google Scholar
M. Coscia, C. Vitale, S. Peola et al., “Dysfunctional Vγ9Vδ2 T cells are negative prognosticators and markers of dysregulated mevalonate pathway activity in chronic lymphocytic leukemia cells,” Blood, vol. 120, no. 16, pp. 3271–3279, 2012.
View at: Publisher Site | Google Scholar
B. N. Lee, H. Gao, E. N. Cohen et al., “Treatment with lenalidomide modulates T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia,” Cancer, vol. 117, no. 17, pp. 3999–4008, 2011.
View at: Publisher Site | Google Scholar
G. D’Arena, V. Simeon, L. De Martino et al., “T-cell modulation by green tea in chronic lymphocytic leukemia,” International Journal Immunopathology Pharmacology, vol. 26, pp. 117–125, 2013.
View at: Publisher Site | Google Scholar
G. D’Arena, L. Laurenti, M. Coscia et al., “Complementary and alternative medicine use in patients with chronic lymphocytic leukemia: an Italian multicentric survey,” Leukemia & Lymphoma, vol. 55, no. 4, pp. 841–847, 2014.
View at: Publisher Site | Google Scholar
Z.-Z. Yang, A. J. Novak, S. C. Ziesmer, T. E. Witzig, and S. M. Ansell, “Attenuation of CD8⁺ T-cell function by CD4⁺CD25⁺ regulatory T cells in B-cell non-Hodgkin’s lymphoma,” Cancer Research, vol. 66, no. 20, pp. 10145–10152, 2006.
View at: Publisher Site | Google Scholar
N. A. Marshall, L. E. Christei, L. R. Murro et al., “Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma,” Blood, vol. 103, no. 5, pp. 1755–1762, 2004.
View at: Publisher Site | Google Scholar
S. Schreck, D. Friebel, M. Buettner et al., “Prognostic impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma,” Hematological Oncology, vol. 27, no. 1, pp. 31–39, 2009.
View at: Publisher Site | Google Scholar
A. Tzankov, C. Meier, P. Hirschmann, P. Went, S. A. Pileri, and S. Dirnhofer, “Correlation of high numbers of intratumoral FOXP3⁺ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma,” Haematologica, vol. 93, no. 2, pp. 193–200, 2008.
View at: Publisher Site | Google Scholar
T. Alvaro, M. Lejeune, M. T. Salvado et al., “Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells,” Clinical Cancer Research, vol. 11, no. 4, pp. 1467–1473, 2005.
View at: Publisher Site | Google Scholar
M. Garcia, B. Bellosillo, B. Sánchez-González et al., “Study of regulatory T-cells in patients with gastric Malt lymphoma: influence on treatment response and outcome,” PLoS One, vol. 7, no. 12, article e51681, 2012.
View at: Publisher Site | Google Scholar
C. Chang, S. Y. Wu, Y. W. Kang et al., “High levels of regulatory T cells in blood are a poor prognostic factor in patients with diffuse large B-cell lymphoma,” American Journal Clinical Pathology, vol. 144, pp. 935–944, 2015.
View at: Publisher Site | Google Scholar
A. F. Koreishi, A. J. Saenz, D. O. Persky et al., “The role of cytotoxic and regulatory T-cells in relapsed/refractory Hodgkin lymphoma,” Apllied Immunohistochemistry & molecular Morphology, vol. 18, pp. 206–211, 2010.
View at: Publisher Site | Google Scholar
W. Y. Kim, Y. K. Jeon, T. M. Kim et al., “Increased quantity of tumor-infiltrating FOXP3-positive regulatory T cells is an independent predictor for improved clinical outcome in extranodal NK/T-cell lymphoma,” Annals Oncology, vol. 20, pp. 1688–1696, 2009.
View at: Publisher Site | Google Scholar
J. Carreras, A. Lopez-Guillermo, B. C. Fox et al., “High numbers of tumor-infiltrating FOXP3-positive regulatory T-cells are associated with improved overall survival in follicular lymphoma,” Blood, vol. 108, no. 9, pp. 2957–2964, 2006.
View at: Publisher Site | Google Scholar
R. H. Prabhala, P. Neri, J. E. Bae et al., “Dysfunctional T regulatory cells in multiple myeloma,” Blood, vol. 107, no. 1, pp. 301–304, 2006.
View at: Publisher Site | Google Scholar
G. D’Arena, G. Rossi, L. Laurenti et al., “Circulating regulatory T-cells in monoclonal gammopathies of uncertain significance and multiple myeloma: in search of a role,” Journal of Immunology Research, vol. 2016, Article ID 9271469, 7 pages, 2016.
View at: Publisher Site | Google Scholar
M. Beyer, M. Kochanek, T. Giese et al., “In vivo peripheral expansion of naive CD4⁺ CD25^high FoxP3⁺ regulatory T cells in patients with multiple myeloma,” Blood, vol. 107, no. 10, pp. 3940–3949, 2006.
View at: Publisher Site | Google Scholar
S. Feyler, M. von Lilenfeld-Toal, S. Jarmin et al., “CD4⁺ CD25⁺ FoxP3⁺ regulatory T cells are increased whilst CD3⁺ CD4⁻ CD8⁻ αβTCR⁺ double negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden,” British Journal of Haematology, vol. 144, no. 5, pp. 686–695, 2009.
View at: Publisher Site | Google Scholar
R. Gupta, P. Ganeshan, M. Hakim, R. Verma, A. Sharma, and L. Kumar, “Significantly reduced regulatory T cell population in patients with untreated multiple myeloma,” Leukemia Research, vol. 35, no. 7, pp. 874–878, 2011.
View at: Publisher Site | Google Scholar
K. R. Muthu Raja, L. Rihova, L. Zahradova, M. Klincova, M. Penka, and R. Hajek, “Increased T regulatory cells are associated with adverse clinical features and predict progression in multiple myeloma,” PLoS One, vol. 7, no. 10, article e47077, 2012.
View at: Publisher Site | Google Scholar
K. Giannopoulos, W. Kaminska, I. Hus, and A. Dmoszynska, “The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterization of immune status in multiple myeloma,” British Journal of Cancer, vol. 106, no. 3, pp. 546–552, 2012.
View at: Publisher Site | Google Scholar
M. Foglietta, B. Castella, S. Mariani et al., “The bone marrow of myeloma patients is steadily inhibited by a normal-sized pool of functional regulatory T cells irrespective of the disease status,” Haematologica, vol. 99, no. 10, pp. 1605–1610, 2014.
View at: Publisher Site | Google Scholar
K. Bhattacharya, S. Chandra, and C. Mandal, “Critical stoichiometric ratio of CD4⁺ CD25⁺ FoxP3⁺ regulatory T cells and CD4⁺ CD25⁻ responder T cells influence immunosuppression in patients with B-cell acute lymphoblastic leukaemia,” Immunology, vol. 142, pp. 124–139, 2013.
View at: Publisher Site | Google Scholar
C.-P. Wu, X. Quing, H. Zhu, and H.-Y. Zhou, “Immunophenotype and increased presence of CD4⁺CD25⁺ regulatory T cells in patients with acute lymphoblastic leukemia,” Oncology Letters, vol. 3, no. 2, pp. 421–424, 2012.
View at: Publisher Site | Google Scholar
X. Wang, J. Zheng, J. Liu et al., “Increased population of CD4⁺CD25^high regulatory T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid leukemia patients,” European Journal of Haematology, vol. 75, no. 6, pp. 468–476, 2005.
View at: Publisher Site | Google Scholar
S. Z. Idris, N. Hassan, L. J. Lee et al., “Increased regulatory T cells in acute lymphoblastic leukemia patients,” Hematology, vol. 20, no. 9, pp. 523–529, 2015.
View at: Publisher Site | Google Scholar
A. M. Zahran, H. Badrawy, and A. Ibrahim, “Prognostic value of regulatory T cells in newly diagnosed chronic myeloid leukemia patients,” International Journal of Clinical Oncology, vol. 19, no. 4, pp. 753–760, 2014.
View at: Publisher Site | Google Scholar
J. M. Rojas, L. Wang, S. Owen, K. Knight, S. J. Watmough, and R. E. Clark, “Naturally occurring CD4⁺ CD25⁺ FOXP3⁺T-regulatory cells are increased in chronic myeloid leukemia patients not in complete cytogenetic remission and can be immunosuppressive,” Experimental Hematology, vol. 38, no. 12, pp. 1209–1218, 2010.
View at: Publisher Site | Google Scholar
E. Nadal, M. Garin, J. Kaeda, J. Apperley, R. Lechlir, and F. Dazzi, “Increased frequencies of CD4⁺CD25^high Tregs correlate with disease relapse after allogeneic stem cell transplantation for chronic myeloid leukemia,” Leukemia, vol. 21, no. 3, pp. 472–479, 2007.
View at: Publisher Site | Google Scholar
I. Hus, J. Tabarkiewicz, M. Lewandowska et al., “Evaluation of monocyte-derived dendritic cells, T regulatory and Th17 cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors,” Folia Histochemistry Cytobiologica, vol. 49, no. 1, pp. 153–160, 2011.
View at: Publisher Site | Google Scholar
C. R. Hasselbalch, M. K. Jensen, K. M. Brimnes et al., “Increase in circulating CD4⁺CD25⁺Foxp3⁺ T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α,” Blood, vol. 118, pp. 2170–2173, 2011.
View at: Publisher Site | Google Scholar
M. Kovacsovics-Bankowski, T. W. Kelley, O. Efimova et al., “Changes in peripheral blood lymphocytes in polycythemia vera and essential thrombocythemia patients treated with pegylated-interferon alpha and correlation with JAK2^V617F allelic burden,” Experimental Hematology & Oncology, vol. 5, p. 28, 2016.
View at: Publisher Site | Google Scholar
M. Massa, R. Campanelli, G. Fois et al., “Reduced frequency of circulating CD4⁺CD25^brightCD127^lowFOXP3⁺ regulatory T cells in primary myelofibrosis,” Blood, vol. 128, no. 12, pp. 1660–1662, 2016.
View at: Publisher Site | Google Scholar
M. Massa, V. Rosti, R. Campanelli, G. Fois, and G. Barosi, “Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib,” Leukemia, vol. 28, no. 2, pp. 449–451, 2014.
View at: Publisher Site | Google Scholar
J. C. Wang, H. Sindhu, C. Chen et al., “Immune derangements in patients with myelofibrosis: the role of Treg, Th17, and sIL2Rα,” PLoS One, vol. 10, no. 3, article e0116723, 2015.
View at: Publisher Site | Google Scholar
S. P. Yajnanarayana, T. Stubig, I. Cornez et al., “JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms,” British Journal of Haematology, vol. 169, no. 6, pp. 824–833, 2015.
View at: Publisher Site | Google Scholar
K. Wang and A. T. Vella, “Regulatory T cells and cancer: a two-sided story,” Immunology Investigation, vol. 45, no. 8, pp. 797–812, 2016.
View at: Publisher Site | Google Scholar
K. Giannopoulos, M. Schmitt, M. Kowal et al., “Characterization of regulatory T cells in patients with B-cell chronic lymphocytic leukemia,” Oncology Report, vol. 20, pp. 677–682, 2008.
View at: Publisher Site | Google Scholar
E. Bachy, J. Bernaud, P. Roy, D. Rigal, and F. E. Nicolini, “Quantitative and functional analyses of CD4⁺CD25⁺FoxP3⁺ regulatory T cells in chronic phase chronic myeloid leukaemia patients at diagnosis and on imatinib mesylate,” British Journal of Haematology, vol. 153, pp. 129–143, 2011.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2017 Giovanni D’Arena et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

2700

Downloads

1234

Citations